This invention relates to a process for the preparation of highly pure 4-(cyclopropylcarbonyl)-α,α-dimethylphenylacetic acid of Formula I, a key intermediate useful in the preparation of highly pure Terfenadine carboxylate. 
Terfenadine carboxylate is a non-sedative antihistaminic compound. It is reported to be a specific H2-receptor antagonist that is also devoid of any anticholinergic, antiserotoninergic, and antiadrenergic effects.
Piperidine derivatives related to terfenadine carboxylate are disclosed in U.S. Pat. No. 4,254,129 and U.S. Pat. No. 4,254,130. In these patents, α,α-dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenyl methyl)-1-piperidinyl]butyl]benzeneacetic acid of Formula III is prepared by alkylation of a substituted piperidine derivative of Formula IV with an ω-haloalkyl substituted phenyl ketone of Formula V wherein halo is a halogen atom, such as, chlorine, bromine or iodine, and alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, followed by reduction of the ketone group and subsequent base hydrolysis.
Preparation of compounds of Formula V is achieved by reacting α,α-dimethylphenylacetic acid alkyl esters with 4-halobutyryl halide under general conditions of Friedel-Crafts acylation. U.S. Pat. No. 4,254,130 describes the preparation of ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate by reaction of 4-chlorobutyryl chloride, aluminum chloride and ethyl α,α-dimethylphenylacetate in carbon disulfide. However, the described reaction results in virtually inseparable mixture of monosubstituted aromatic para and meta regioisomers of the Formula VI where unwanted meta isomer predominates to about 65%. 
CA Patent 2,118,188 discloses a process, which has proved to be more selective in the formation of para isomer. In this process, Friedel-Crafts acylation has been carried out on the derivative of Formula VII with 4-chlorobutyryl chloride as the acylating agent in carbon disulfide in the presence of aluminum chloride and the corresponding para acylated product has been obtained that contains no more than 10% of meta isomer. The presence of meta isomer at this stage results in an unacceptable level of meta isomer in terfenadine carboxylate and once again it is difficult to achieve pharmaceutically pure product from such a mixture. This requires time consuming purification processes which are wasteful of material and costly.
U.S. Pat. No. 5,578,610 provides a procedure wherein the mixture of regioisomers of Formula VI has been transformed to another mixture of para and meta regioisomers of Formula VIII and subsequently the substantially pure para regiosiomer is obtained by fractional crystallization of the corresponding cinchonidine salt. This process exhibits several disadvantages such as use of expensive cinchonidine, its toxicity, low yield and in addition to that, two isolation steps are necessary to obtain the desired product of Formula I.
U.S. Pat. No. 6,147,216 provides an alternate technique to obtain enriched para regioisomer by high vacuum fractional distillation of methyl or ethyl ester of the mixture of isomeric acids of Formula VIII followed by repeated fractional crystallization at low temperatures. This process is operationally tedious, inefficient, yields are low and therefore, is not amenable to industrial scale.
The aim of the present invention is to provide an efficient method to obtain highly pure 4-(cyclopropylcarbonyl)-α,α-dimethylphenylacetic acid of Formula I, which is an useful intermediate for the preparation of pharmaceutically highly pure antihistaminic piperidine derivatives.